Cells maintain concentration gradients of certain ions across their membranes. For example, cells have a lower sodium ion concentration and a higher potassium ion concentration inside the cell than that outside the cell. The concentration gradient of ions across the cell membrane and the selective permeability of the membrane results in the negative resting potential of the cell. Voltage-gated ion channels open in response to a perturbation of the resting potential of the cell and allow ions to flow into or out of the cell in the direction of lower concentration.
Voltage-gated ion channels are involved in many cellular processes. For example, nerve cells maintain a negative resting potential when not transmitting an electrical impulse. When an excitatory synaptic signal occurs, depolarization causes voltage-gated sodium channels to open. Since the concentration of sodium ions outside the cell is much higher than that inside the cell, positively charged sodium ions flow into the cell causing a further depolarization of the cell membrane. Voltage-gated potassium ion channels, for example, Shaker class Kv1.x-Kv4.x channels, also open in response to depolarization and are responsible for restoring the cell to its resting potential. Since the potassium ion concentration inside the cell is higher than that outside the cell, the positively charged potassium ions flow out of the cell and bring the cell back to its resting potential.
Because voltage-gated potassium ion channels are responsible for returning neurons to their resting potential, agents that prolong the length of time that the channel remains open, or potentiate channel activity, are expected to be useful in treating disorders characterized by abnormally high electrical activity, such as seizures and cardiac arrhythmias. However, for the majority of voltage-gated potassium ion channels, there are no known compounds that prolong the opening of the channel. Conversely, agents that decrease the length of time that the channel remains open, or inhibit channel activity, are expected to be useful in treating disorders that are characterized by loss of conductivity in neurons, such as multiple sclerosis or demyelination due to injury.
In addition, the activation of voltage-gated potassium ion channels is involved in mediating the immune response to an antigen. Therefore, inhibitors of these channels are expected to be therapeutically useful in suppressing graft rejection by inhibiting the immune response, and potentiators are expected to help stimulate immune response in cases where it is pathologically depressed.